Eshita Khera1, Liang Zhang1, Sheryl Roberts2, Ian Nessler1, Darleen Sandoval3, Thomas Reiner2,4,5, Greg M Thurber6,7. 1. Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan. 2. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. 3. Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan. 4. Department of Radiology, Weill Cornell Medical College, New York, New York. 5. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York; and. 6. Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan gthurber@umich.edu. 7. Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
Abstract
The diabetes community has long desired an imaging agent to quantify the number of insulin-secreting β-cells, beyond just functional equivalents (insulin secretion), to help diagnose and monitor early stages of both type 1 and type 2 diabetes mellitus. Loss in the number of β-cells can be masked by a compensatory increase in function of the remaining cells. Since β-cells form only about 1% of the pancreas and decrease as the disease progresses, only a few imaging agents, such as exendin, have demonstrated clinical potential to detect a drop in the already scarce signal. However, clinical translation of imaging with exendin has been hampered by pancreatic uptake that is higher than expected in subjects with long-term diabetes who lack β-cells. Exendin binds glucagonlike peptide-1 receptor (GLP-1R), previously thought to be expressed only on β-cells, but recent studies report low levels of GLP-1R on exocrine cells, complicating β-cell mass quantification. Methods: Here, we used a GLP-1R knockout mouse model to demonstrate that exocrine binding of exendin is exclusively via GLP-1R (∼1,000/cell) and not any other receptor. We then used lipophilic Cy-7 exendin to selectively preblock exocrine GLP-1R in healthy and streptozotocin-induced diabetic mice. Results: Sufficient receptors remain on β-cells for subsequent labeling with a fluorescent- or 111In-exendin. Conclusion: Selective GLP-1R blocking, which improves contrast between healthy and diabetic pancreata and provides a potential avenue for achieving the long-standing goal of imaging β-cell mass in the clinic.
The diabetes community has long desired an imaging agent to quantify the number of insulin-secreting β-cells, beyond just functional equivalents (insulin secretion), to help diagnose and monitor early stages of both type 1 and type 2 diabetes mellitus. Loss in the number of β-cells can be masked by a compensatory increase in function of the remaining cells. Since β-cells form only about 1% of the pancreas and decrease as the disease progresses, only a few imaging agents, such as exendin, have demonstrated clinical potential to detect a drop in the already scarce signal. However, clinical translation of imaging with exendin has been hampered by pancreatic uptake that is higher than expected in subjects with long-term diabetes who lack β-cells. Exendin binds glucagonlike peptide-1 receptor (GLP-1R), previously thought to be expressed only on β-cells, but recent studies report low levels of GLP-1R on exocrine cells, complicating β-cell mass quantification. Methods: Here, we used a GLP-1R knockout mouse model to demonstrate that exocrine binding of exendin is exclusively via GLP-1R (∼1,000/cell) and not any other receptor. We then used lipophilic Cy-7 exendin to selectively preblock exocrine GLP-1R in healthy and streptozotocin-induced diabeticmice. Results: Sufficient receptors remain on β-cells for subsequent labeling with a fluorescent- or 111In-exendin. Conclusion: Selective GLP-1R blocking, which improves contrast between healthy and diabetic pancreata and provides a potential avenue for achieving the long-standing goal of imaging β-cell mass in the clinic.
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